Antiviral therapies are lacking or inadequate for many clinically relevant viruses, such as the Flaviviridae dengue and West Nile Virus. Host-targeted antivirals can provide an effective strategy to treat viral infections. The aim of the proposed research and overall career development plan is to identify specific, rational host targets for broad-acting antiviral design. The candidate is a physician-scientist with an extremely strong commitment to basic science research whose long term career goal is to become an independent investigator in the field of host-virus interactions and to make meaningful contributions to the development of improved antiviral therapy. Specifically, she hopes to contribute to our understanding of the mechanism driving host interferon-mediated antiviral response. The candidate's short term career goals are (1) to become proficient in new genetic, biochemical, and virological techniques; (2) to apply those techniques toward identifying the mechanism of interferon antiviral effects; (3) to develop professional expertise in fostering productive collaborations between experts in virology, genetics, cellular biology, and systems biology; and (4) to produce sufficient preliminary data and publications to apply competitively for R01 funding as the basis of a career in academic medical research. The overall theme of the proposed project is to understand how interferon-? (IFN?) inhibits Flaviviridae. The host molecule IFN? is one of the broadest acting antivirals known. To better understand how IFN? inhibits viral infection, a genome-wide small interfering RNA screen was performed to identify interferon effector genes that inhibit fully infectious HCV. The screen identified PPAR? DNA binding domain interacting protein 1 (PDIP1) as a top scoring IFN effector. The mechanism of PDIP1 antiviral activity is wholly unknown. The specific aims of this study are to test two fundamental hypotheses: 1) a discrete set of host IEGs such as PDIP1 have broad, clinically relevant antiflaviviral activity that is active downstream of viral impedance and 2) the IEG PDIP1 mediates broad antiviral effects through depletion of host lipids required for viral replication. Te proposed work will be pursued within the context of a structured career development program which will allow the candidate to acquire expertise in genetic, biochemistry, and cellular biology approaches to studying host antiviral defense. These studies will be supported by the highly collaborative mentorship of Dr. Raymond Chung, a hepatitis C virologist, in collaboration with Dr. Stephen Elledge, a geneticist, and Dr. Tetsurou Satoh, a PDIP1 expert, with input from Dr. Ramnik Xavier, an expert systems biologist, who will together form a formal research advisory committee for the candidate. The research environment includes the dynamic research community of the MGH GI Division and Harvard Medical School faculty and will provide an enriching, inspiring and supportive climate in which Dr. Fusco will be able to achieve her full potential as an independent, R01-funded investigator.